Inhibiting PI3K and MAPK Pathways: Clinical Response in PTEN Syndrome : Journal of Vascular Anomalies

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Case Report

Inhibiting PI3K and MAPK Pathways

Clinical Response in PTEN Syndrome

Liu, Lucy Y.a; Jeng, Michael R.b; Teng, Joyce M. C.a

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Journal of Vascular Anomalies: September 2022 - Volume 3 - Issue 3 - p e047
doi: 10.1097/JOVA.0000000000000047
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Extracranial arteriovenous malformations (AVMs) are high-flow congenital vascular anomalies. Although rare, AVMs are often associated with significant morbidity and mortality, and there are currently no Food and Drug Administration-approved treatments. Several inherited syndromes are known to have high risk of developing AVMs, such as phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS). Non-syndromic extracranial AVMs on the other hand are shown to result from somatic mutations, most commonly MAP2K1, providing potential therapeutic targets.1 Understanding the signaling pathways of these genetic variants has provided insight into the management of complex AVMs. This case report highlights a patient with PHTS treated with sirolimus and trametinib as combined targeted therapy.

Case report

An 8-year-old boy presented with a large extracranial AVM extending from the pelvis to the distal left leg, with hemihypertrophy of the entire left leg. He also had 2 smaller fast flow vascular lesions on the right calf and palm that were excised surgically. At age 10, he experienced palpitations and severe dyspnea on exertion and was diagnosed with moderate left ventricular dilatation secondary to AVM-induced volume overload, prompting multiple embolizations over the next few years. He was also found with macrocephaly and developmental delay.

At 12 years, he developed frequent episodes of arrhythmia due to dilated cardiomyopathy and required Holter monitoring. He was unable to ambulate for 15 minutes without dyspnea or palpitations. Whole exome sequencing of tissue and peripheral blood revealed a germline deletion of exons 6–9 in the PTEN gene, supporting the diagnosis of PHTS. He was started on sirolimus at 0.8 mg/m2 twice daily at 12 years of age and maintained therapeutic sirolimus trough levels (12–15 µg/dL). Additional embolizations were performed. He was intermittently noncompliant to sirolimus, during which his symptoms significantly worsened with decreased tolerance to physical activities and pain. The flares of dyspnea and fatigue improved after re-starting sirolimus. Over the next 4 years, however, his cardiac dysfunction progressed with increased fatigue, exercise intolerance, and developed chronic painful skin ulcers and cellulitis of his left calf, requiring repeated courses of antibiotics and hospital admissions for pain management. Skin targeted wound care, including unna boots, dermagrafts, and low dose pulsed-dye laser, provided no clinical improvement.

A MAP kinase kinase (MEK) inhibitor, trametinib at 0.5 mg daily (0.007 mg/kg/d), was added to sirolimus at age 16, 4 years after initiation of sirolimus, with the objective to control proliferation, angiogenesis, and disease burden from his AVM. He tolerated the therapy well, with a mild acneiform eruption on the face that subsided quickly with topical benzoyl peroxide wash, topical clindamycin, and tretinoin. Trametinib dose was subsequently escalated to 2 mg daily (0.02 mg/kg/d). The patient tolerated the dual treatment well for more than 32 months to date. His leg swelling and exercise intolerance worsens intermittently, requiring adjustment of furosemide dose and emphasis of sirolimus compliance, with trough level monitoring every 2–3 months. His AVM and cardiac disease have stabilized. Despite having occasional palpitations, he has preserved systolic function and sinus rhythms on repeated cardiac evaluations. The patient is now able to run twice weekly and play soccer for 90 minutes weekly. His lower extremity ulcers have healed completely, and confluent hair regrowth was noted on the distal leg, suggesting that venous stasis and tissue ischemia from his AVM have largely resolved.

The patient continues to have regular surveillance ophthalmology exams, comprehensive laboratory surveillance, and cardiac follow-ups without any signs of drug-induced toxicities. The mild acneiform eruption, a common cutaneous side effect associated with mammalian target of rapamycin (mTOR) and MEK inhibitors, has been well controlled with benzoyl peroxide wash, tretinoin cream, and clindamycin lotion. He was previously on rivaroxaban for pain during pulmonary glue embolization and following interventional radiology procedures but has since been able to stop the medication. He has even become gainfully part time employed. Finally, his leg size has decreased to the point that smaller compression garments were needed.


The management of this case was challenging due to severity of the AVM and cardiac comorbidity. This case highlights the critical role of targeted medical approach in the management of complex vascular anomalies. Although conventional surgical treatments including embolization and excision are beneficial for smaller AVMs, recurrence is often rapid for complex cases. Given our patient’s rapidly progressive cardiomyopathy despite interventional surgeries and mTOR inhibition, alternative systemic medical therapy was necessary.

The tumor suppressor gene, PTEN, plays a key role regulating both phosphoinositide 3-kinases/AKT/mTOR (phosphoinositide 3-kinases) and RAF/MEK/ERK (MAPK) signaling pathways.2 Loss of PTEN function, therefore, will result in activation of both pathways leading to cell proliferation and increased angiogenesis. Dysregulation of either or both pathways are known to associate with development of malignancy3 as well as AVMs. Although blockade of both pathways simultaneously has been considered within the oncology literature, it has not been proposed in the treatment of vascular anomalies. Another concern about the dual therapy arises from the known cardiac toxicity of trametinib, particularly as the patient has already developed cardiomyopathy and arrhythmia as a result.

Sirolimus and trametinib individually have been reported as off-label targeted treatments for vascular anomalies, including AVM.4,5 Sirolimus is one of the most commonly used agents for off-label treatment of both vascular tumors and malformations, including aggressive AVMs.4 Trametinib has also been used as a targeted treatment for extracranial AVM in a patient with a somatic mutation in MAP2K1, which encodes MEK1 and inhibits the MAPK pathway.5 Due to clinical experience and efficacy profile, we initiated sirolimus first. The gradual clinical progression is likely due to the sustained activation of MAPK pathway due to loss of PTEN function. Simultaneous inhibition of both pathways may have synergistic effects to stabilize and treat progressive AVM, although additional studies are needed to investigate dual therapy versus monotherapy. Given the patient’s overall improvement with combined low dose dual therapy as well as intermittent worsening secondary to reduced compliance of sirolimus, there has not been an attempt on proactive withdrawal of sirolimus. Our knowledge about the pharmacokinetics of dual treatment is limited. Therefore, dose escalation should proceed with caution, and vigilant clinical monitoring is recommended, especially for young children (Figure 1).

Figure 1.:
Progression of hypertrophy of left lower extremity from (A) 2015 to (B) 2017, with (C) development of ulcerations (inset), now healed. D, magnetic resonance imaging from 2019, which showed a large arteriovenous malformation with diffuse hypertrophy of the left lower extremity.


To our knowledge, this is the first reported case of extracranial complex AVM due to PTEN mutation treated with combination targeted therapy, using mTOR and MEK inhibitors. Although combination therapy may increase the risk of toxicity, our pediatric patient was able to tolerate combined used of low dose medications well with mild cutaneous toxicities only and much improved physical performance status for over 2 years. There are multiple mTOR and MEK inhibitors on the market currently for oncologic disorders. The overlapping genetic changes between cancer and vascular anomalies suggest the importance of a potential genetic-guided personalized approach in the management of complex vascular malformations. However, larger scale and well-designed prospective studies are needed to determine the safety and long-term efficacy of these targeted treatments. Optimal dosing and therapeutic duration also need to be defined in future studies.


We would like to acknowledge all members of our Vascular Anomalies team. We would further like to thank especially Dr Anne Marqueling, Dr Shellie Josephs, and Dr David Hovsepian in the care of this patient.

Previous Presentations: This case report was presented at the ISSVA Debates & Updates Meeting, Vascular Anomalies in a Changing World, May 13–15, 2021.


1. Al-Olabi L, Polubothu S, Dowsett K, et al. Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy. J Clin Invest. 2018;128:1496–1508.
2. Milella M, Falcone I, Conciatori F, et al. PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer. Sci Rep. 2017;7:43013.
3. De Luca A, Maiello MR, D’Alessio A, Pergameno M, Normanno N. The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches. Expert Opin Ther Targets. 2012;16(Suppl 2):S17–S27.
4. Triana P, Dore M, Cerezo VN, et al. Sirolimus in the treatment of vascular anomalies. Eur J Pediatr Surg. 2017;27:86–90.
5. Lekwuttikarn R, Lim YH, Admani S, Choate KA, Teng JMC. Genotype-guided medical treatment of an arteriovenous malformation in a child. JAMA Dermatol. 2019;155:256–257.

Arteriovenous malformation; Trametinib; Sirolimus; PTEN; Vascular anomaly

Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The International Society for the Study of Vascular Anomalies.